Chemical methods will be developed for the synthesis of four classes of pyrimidine nucleosides containing substitutions in both the sugar moiety and in the aglycon which may exhibit selective activity against several herpes viruses and against human tumors with minimal toxicity against normal cells. The basis of this specificity may be the nonspecific nucleoside kinase(s) carried or induced by the viruses or reported to be present in human tumor cells which could metabolize these compounds to active drugs. Some of these target nucleosides with good leaving groups may exert their biological effects by undergoing neighboring group displacement reactions in vivo ("masked precursors") to liberate the active drug. Radiolabeled 2'-fluoro-5-iodo-ara-C (which already demonstrates potent and selective antiviral activity and selectively inhibits human tumor cells but not normal cells) will be synthesized for the "in-house" biochemical and chemotherapeutic studies. Purine arabino nucleosides of ara-A and ara-G with halogeno groups in the arabinosyl moiety will also be synthesized as potential antiviral and/or anticancer agents. Several glucuronides of anticancer nucleosides will be prepared. These nucleoside-beta-glucuronides are expected to undergo enzymatic cleavage in vivo in tumor tissue rich in beta-glucuronidase to liberate potent drugs. "In-house" antiviral, biochemical, and chemotherapeutic collaborative studies for proper evaluation of nucleosides of all seven classes to be synthesized are described. These studies should lead to the development of new agents superior to those drugs currently available for the treatment of cancer and certain viral diseases in man.